Ischemia-related injury contributes significantly to morbidity and mortality throughout the world, with perhaps cardiac and cerebral ischemia-related injuries being the most well-known (such as but not limited to heart attack and stroke). Ischemic heart disease is a leading cause of death in North America and is predicted to become more prevalent as the population ages (Scroggins, 2001). Ischemia and reperfusion lead to tissue damage through a variety of mechanisms. For example, ischemia and reperfusion profoundly affect mitochondria and the cytosol. Current therapies for ischemic disease are directed at the restoration of blood flow to the ischemic region. However, during reperfusion additional damage related to generation of reactive oxygen species occurs (Singh et al (1995) Mol Cell Biochem 147:77-81 and Flaherty et al (1998) Free Radic. Biol. Med. 5:409-419; herein incorporated by reference in their entirety).
The transient receptor potential vanilloid-1 (TRPV1) is a capsaicin responsive ligand-gated cation channel selectively expressed on small, unmyelinated peripheral nerve fibers (cutaneous nociceptors). See Caterina and Julius (2001) Annu Rev Neurosci 24:487-517 and Montell et al (2002) Mol. Cell. 9:229-231, herein incorporated by reference in their entirety.
Capsaicin, a pungent substance derived from the plants of the solanaceae family (hot chili peppers) has been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers, C-fibers and A-delta fibers that may be involved with signaling pain. Therapeutically capsaicin has been used as a topical analgesic. See for example U.S. Pat. Nos. 4,997,853; 5,063,060; 5,178,879; 5,296,225; 5,665,378; 6,248,788; 6,239,180; and 4,599,342; herein incorporated by reference in their entirety. Capsaicin binds and activates TRPV1.